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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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July 12, 2013

Clinical Trial Fraud Uncovered

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Posted by Derek

Hmmm. This article from Bloomberg says that the BMS/Pfizer anticoagulant Eliquis (apixaban), a Factor Xa inhibitor approved late last year by the FDA, was delayed for months because of misconduct in its Chinese clinical trials. (Its clinical trials had not been without incident even before this). Documents posted by the FDA have the details. Says the article:

In the Eliquis trial, Bristol-Myers hired Pharmaceutical Product Development Inc., a closely held, Wilmington, North Carolina, company known as PPD, to help oversee it.

The Eliquis trial was questioned on two issues, according to the FDA documents first cited by the journal Pharmaceutical Approvals Monthly. One was the improper manipulation of records at a study site for 35 patients at the Shanghai 9th Peoples Hospital in China. The second involved the high percentage of the 9,000 patients who were supposed to be getting Eliquis, and instead were either given the wrong drug, or the wrong dose.

There was a broad list of issues at the Shanghai hospital, according to FDA documents. They included failure to report four potential adverse medical events, late reports on three others and three medical outcomes that weren’t included in the data. Additionally, some patient names and dates were wrong, and Chinese and English records didn’t match in some cases. The FDA also reported that some patient records disappeared just ahead of a site visit by agency inspectors.

I wonder if the Bloomberg reporter was tipped off to this himself, because you have to dig into this PDF (which is one of many) to find the goods (do a search for the words "Shanghai" and "fraud"). Here are some quotes from the document itself:

Although BMS contracted with a Contract Research Organization, PPD, to provide site monitoring for ARISTOTLE, PPD did not have a presence in the People’s Republic of China when the trial was initiated in PRC; BMS initially used its own employees for monitoring. One BMS employee along with at least one other individual altered subject records after being notified the site would be inspected by OSI. OSI inspected eight clinical sites worldwide after becoming aware of this action. Additionally, after errors in dispensing study drug became an issue, BMS and PPD, a CRO involved in conducting and monitoring ARISTOTLE, were inspected specifically to review the issue of trial oversight and monitoring. OSI concludes that the study appears to have been conducted and monitored adequately. They did recommend that data from sites in China be excluded because the employee who committed the GCP violation in China was involved in the conduct of the trial at all Chinese sites.

This came to light because a contract worker went to his or her supervisors with a problem: this person had been asked to change data and documentation on a hard drive before an FDA inspection, and the supervisor making the request (who was later fired) had worked at 18 other trial locations in China. This led the FDA, naturally enough, to say that it was worried about what else might have been going on, and to complain about broad problems with oversight.

As shown in the FDA documents, the agency went on to run the data with that specific site excluded, and then with all the other Chinese site data excluded, and the analysis still came out in favor of apixaban (although not as robustly in some categories). So the approval of the drug seems to have been the right call; the conclusions of the trial don't seem to have been switched by the misconduct. Still, you don't want this sort of thing.

Elliot Levy of BMS is quoted several times in the Bloomberg article, generally playing down the problems mentioned by the FDA: "not exceptional", "appropriately documented and reported", and so on. But if everything was normal, why did things stall for nine months? The lead outside investigator on the trial, Christopher Granger of Duke, has a different perspective:

“There is a greater likelihood of some of this impropriety in certain regions,” Granger said in a telephone interview. “We’ve had experiences in India and China where we’ve had more than we would have expected.”

Unfortunately, I think that's a fair assessment. But it doesn't have to be that way. There are vast numbers of ethical, hard-working scientists and staff in both India and China; it's not like these entire countries are full of cheaters and corner-cutters. But international companies go to these countries to get work done for lower cost, so the incentives are there to keep those costs down by whatever means come to hand. There are underhanded shortcutters in every country in the world, but some business environments give these people more scope to exercise their talents.

I'm actually glad when this sort of thing comes to light. Although it's not like Bristol-Myers Squibb or Lilly were rushing to do that, were they? I think that the only way to clean up this kind of behavior is to make it public, so that it has as many consequences as possible. If a country's reputation for doing fast, cost-effective clinical trials is compromised by a reputation for regulatory trouble and unreliable data, well, that's another set of incentives at work, but this time in the right direction. Throwing a towel over these incidents does no one any good in the long run. Make it public; make it sting.

Comments (10) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | The Dark Side


COMMENTS

1. Anonymous Big Pharma Researcher on July 12, 2013 4:23 PM writes...

Here is another very interesting passage from that PDF file: "Notably, ARISTOTLE was planned as a non-inferiority study. In this type of the study, “noise” resulting from sloppiness in execution tends to favor success by minimizing apparent differences between the experimental agent and the control. This is the opposite of the effects of noise in superiority studies, where noise tends to obscure the differences that one hopes to find."

In the long term, science is best served by well-designed, head-to-head, superiority studies with clear endpoints.

Permalink to Comment

3. Yokono on July 13, 2013 11:02 AM writes...

I wonder if this has anything to do with the surprising decision of BMS' Head of Research to retire in somehow of a rush mode and transitioning to someone that does not seem to have the right credentials for the job.

Permalink to Comment

4. Anonymous on July 13, 2013 11:49 AM writes...

Quoting: "Granger said in a telephone interview. “We’ve had experiences in India and China where we’ve had more [improprieties] than we would have expected.”"

Just what is their "expected level of improprieties"? Where I come from (I'm in the United States), the expected level is ZERO.

Permalink to Comment

5. Random RN on July 13, 2013 2:09 PM writes...

What's the problem? Once Obamacare become the law of the land the Health and Human Services will outlaw any medication side effects and everyone will live for a hundred years!

Permalink to Comment

6. Gilligan on July 13, 2013 2:45 PM writes...

"it's not like these entire countries are full of cheaters and corner-cutters"

Well, yes, actually they are. There seems to be something in the Chinese culture that encourages getting over if you can get away with it.

I offer for example the ordinary steel bolts that a manufacturer in Taiwan sold as high strength bolts and which resulted in the engine falling off an airplane at O'Hare airport in the 1980s. There are the various scandals involving poisons being substituted for items intended for human consumption because they were cheaper. When customers started testing protein levels in milk because the sellers were watering it down, the milk sellers added poisonous material to the watered down milk to fool the tests.

I have read the story of a toy company testing and discovering that the Chinese supplier was using lead based paint on children's toys because it was cheaper even though the contract specified that no lead based paint would be used. When the customer supplied the Chinese supplier with safe paint, the Chinese sold that more expensive paint and used lead based paint and pocketed the difference.

The Chinese attitude seems to be that if you trust me enough to let me rip you off, you are stupid and deserve to be ripped off.

Permalink to Comment

7. pgwu on July 13, 2013 10:09 PM writes...

#6: you probably only see one part of the story. If you read the article by Andy Parrett in the April issue of Applied Clinical Trials, perhaps you'll have a more balanced perspective. The author compares the pharma executive as the new emperor and some large CROs as the two tailors. When the tailors cannot do enough themselves, do they hire honest people to do their jobs? It has nothing to do with a particular culture, more to do with a dishonest subculture. Did you vote for the person who did not recall or who did not inhale?

Permalink to Comment

8. Harun on July 14, 2013 12:21 AM writes...

One of the Chinese toy companies in question actually owned their own lead testing equipment, obviously to show to the foreign buyer, but not for real use.

If you are ever in charge of QC for a product made in China, make sure to ask the factory line people for their inspection reports. Make sure the numbers seem realistic - I have seen wood thickness measurements with deviations tighter than you would see for extruded aluminum. (That means they are just filling in random numbers and not actually measuring.) Another trick is to ask if they do final inspections. They will say yes. Then ask to see some inspection reports, and then ask to see example of failed inspection reports. If they actually have failed ispections, that is a very good sign.

Also make sure to take random samples from actual production for testing. Any samples made for testing pre-production will be carefully made and use all the safety paint, etc. And personally, I would not trust Chinese local employees to choose the random samples. Almost better to inform the supplier that payment for shipments will have to wait until arrival in the USA and testing in the USA. There is simply too much money to be offered to inspectors and the like to not corrupt them in subtle ways.

Permalink to Comment

9. Anonymous on July 15, 2013 3:24 PM writes...

The problem is - after all of these examples of fraud, impropriety, bad science and down right cheating - what would have been unacceptable but would lead to a root cause investigation, remediation and overseen by a quality management system in the US - doesn't seem to apply to any of the work performed in China.

It's not rocket science. Wake up Big Pharma - it's your kid who may be the next patient - do you feel safe?

Permalink to Comment

10. Andrew on August 2, 2013 8:45 PM writes...

Its really sad to here that there are many fraud trials done now but we must also give it to those who are working decently and doing their jobs honestly.

Permalink to Comment

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